Various central nervous system (CNS) disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (e.g. 5-HT1A), the 5-HT2 family (e.g. 5-HT2A), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.
The biogenic amine serotonin (5-hydroxytryptamine; 5-HT) is a brain neurotransmitter that has been strongly implicated in the pathophysiology and treatment of a wide variety of neuropsychiatric disorders. It exerts its effects through a diverse family of serotonin receptor subtypes. Of the 14 different mammalian serotonin receptors to have been cloned, all but one are members of the G-protein coupled receptor superfamily. Several of these, including the serotonin 5-HT6 receptor, stimulate adenylyl cyclase via G coupling. 5-HT6 has a high affinity for several therapeutically important antidepressant, antianxiety, hallucinogenic, and antipsychotic drugs, particularly the atypical antipsychotics such as clozapine. The relevance of the 5-HT6 receptor to psychotherapeutics is indicated both through its unique anatomical distribution and pharmacological properties.
The recently identified human 5-HT6 receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyms, and CA1, CA2, and CA3 regions of the hippocampus. Lower levels of 5-HT6 receptor mRNA are seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdalae, and in the cortex. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorder, attention deficit disorder, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer's disease), sleep disorders, feeding disorders (e.g. anorexia, obesity, or bulimia), neurodegenerative disorders (e.g. stroke or head trauma), panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine or benzodiazepines), schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Compounds which interact with, stimulate, or inhibit the 5-HT6 receptor are commonly referred to as 5-HT6 ligands. In particular, 5-HT6 selective ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia, obesity, and bulimia, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, bipolar disorder, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder and irritable bowel syndrome (See for examples. Roth et al., J. Pharmacol. Exp. Ther. 268:1403-14120 (1994), Sibley et al., Mol. Pharmacol. 43:320-327 (1993), Sleight et al., Neurotransmission 11:1-5 (1995), and Sleight et al., Serotonin ID Research Alert 2(3):115-8 (1997)). Furthermore, the effect of 5-HT6 antagonist and 5-HT6 antisense oligonucleotides to reduce food intake in rats has been reported (Bentley et al., Br. J. Pharmacol. Suppl. 126:66 (1999) and Bentley et al., J. Psychopharmacol. Suppl. A64:255 (1997)).
Scientific research has revealed a potential therapeutic use for modulators of the 5-HT6 receptor, especially with regard to various CNS disorders. Blocking 5-HT6 receptor function has been shown to enhance cholinergic transmission (Bentley et al., Br. J. Pharmacol. 126:1537-1542 (1999) and Riemer et al., J. Med. Chem. 46:1273-1276 (2003)). 5-HT6 antagonist have also been shown to reverse cognitive deficits in in vivo cognition models induced by the muscarinic antagonist scopolamine (Woolley et al., Psychopharmacology 170:358-367 (2003) and Foley et al., Neuropsychopharmacology 29:93-100 (2004)).
Studies have shown that 5-HT6 antagonists increase levels of glutamate and aspartate in the frontal cortex and dorsal hippocampus as well as acetylcholine in the frontal cortex. These neurochemicals are known to be involved in memory and cognition (Dawson et al., Neuropsychopharmacology 25(5):662-668 (2001); Gerard et al., Brain Res. 746:207-219 (1997); and Riemer et al., J. Med. Chem. 46(7):1273-1276 (2003)).
Studies have also shown that 5-HT6 antagonist increases the level of dopamine and noradrenaline in the medial prefrontal cortex (Lacroix et al., Synapse 51:158-164 (2004)). In addition, 5-HT6 receptor antagonists have been shown to improve performance in the attentional set shifting task (Hatcher et al., Psychopharmacology 181(2):253-9 (2005)). Therefore, 5-HT6 ligands are expected to be useful in the treatment of disorders where cognitive deficits are a feature, such as schizophrenia. Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor and this may be a factor in their profile of activities (Roth et al., J. Pharm. Exp. Therapeut. 268:1402-1420 (1994); Sleight et al., Exp. Opin. Ther. Patents 8:1217-1224 (1998); Kohen et al., J. Neurochem. 66(1):47-56 (1996); Sleight et al., Brit. J. Pharmacol. 124:556-562 (1998); and Bourson et al., Brit. J. Pharmacol. 125:1562-1566 (1998)).
Stean et al., Brit. J. Pharmacol. 127 Proc. Supplement 131P (1999), have described the potential use of 5-HT6 modulators in the treatment of epilepsy. 5-HT6 receptors have also been linked to generalized stress and anxiety states (Yoshioka et al., Life Sciences 62(17/18):1473-1477 (1998)). 5-HT6 agonists have been shown to elevate levels of GABA in brain regions associated with anxiety and shown positive effects in models predictive of obsessive-compulsive disorder (Schechter et al., NeuroRx. 2(4):590-611 (2005)). The use of modulators for this receptor is therefore expected for a wide range of CNS disorders.
Moreover, a reduction in food intake in rats has been reported using 5-HT6 receptor modulators (Bentley et al., Br. J. Pharmacol. Suppl. 126:66 (1999); Bentley et al. J. Psychopharmacol. Suppl. A64:255 (1997); Pendharkar et al., Society for Neuroscience (2005); Heal et al. Pharmacol. Ther. 117, 207-231 (2008)). 5-HT6 receptor modulators may therefore also be useful in the treatment of feeding disorders like anorexia, obesity, bulimia and similar disorders and also type 2 diabetes.
The importance of psychoactive drugs in present treatment of mental illness, and the presence of serious and undesirable side-effects with their use, makes the development of improved drugs of great interest. Furthermore, the need for a safe, efficacious treatment for obesity is highly desirable. Animal models useful in screening assays provide a benefit by determining candidate agents that have improved specificity of action.
Therefore, the present invention is directed to novel compounds which provide alternatives in overcoming these and other deficiencies in the art.